Steroidal compounds and methods for obtaining the same



Patented a.s,194e s 2,408,834 v v REISSU B UNITED STATES PATENT OFFICE 2,408,834 STEROIDAL CONIPOUNDS AND METHODS FOR OBTAINING THE SAME Romeo B. Wagner, State College, Pa., 'assignor 'to Parke, Davis & Company, Detroit, Mich.;'a cor poratio'n-of Michigan NoDrawing. Application May 15, 1944, Serial No. 535,758 I w '5 Claims. (Cl. 26023915) The invention relates to new steroidal sative steroidal compounds of the typed'erived'from' pogenin type compounds and methods for obthe mammalian suprarenal cortex taining the same. oxygen containing group'in ring 0' of the cyclo- I have obtained for the first time the heretopentanopolyhydrophenanthrene nucleus. fore .unknown steroidal sapogemn compound GENERAL'PROCEDURE FOR OBTAINING A SAPOGENIN hereinafter referred to as rockogen'in which has FRACTION In obtaining the new compounds, the plant or the following structural formula.

part of the same which is to be extracted 'iscut OH: CEBU-Ha OH 4} p up, ground or shredded and then extracted either with hot water or a lower aliphatic alcohol such o-0i as ethyl alcohol. 7

The :plant may be dried before extraction, but

I prefer to extract the plant without any I p preliminary drying. I also prefer to analfi cohol solvent such as ethanol orabout 95% hot I aqueous ethanol. For example, if one "has about X/A/ plants; such as stems, soft roots, leaves or fruit; H these can be covered over with about 32 liters of 1 9:0, two 7-liter portions of hot ethanol and then OH squeezed dry The extract and wash alcohol can y evaporated to a syrup and the syrup con- H cen'trated by passing a current of air over its surand groups hydrolyzable to a agent, the evaporation takes place much more H slowly.

7 After evaporation, the concentrate containing H saponins and like combinations of the steroidal The new compoundsof the invention have the p ni m s be hy r lyzed, in order "to following'general formula, liberate the sapogenins. This is best accom- Y CH. CHECK: plished by aqueous or alcoholic strong mineral on, I on, acid. For'exampl'e, the above mentioned con- Q CHCm centrate from 25 kg. of plant material .can be hyo e, drolyzed by refluxing it 'for'2hours with 3 liters D l 40 of 2N ethanolic hydrochloric acid The reaction J B y c I of hot. alcohol. The combined alcoholic filtrates where x and Y are members of the class =0, are diluted with 20 liters of diethyl ether and the sodiumlghydr-oxide and water and evaporated.

hydrolyzed by refluxing the residue w th 3 voland' r HPS hydrolyzable t0 i lanes of 10% alcoholic potash for 30 minutes.

OH. The cooled mixture from the alkaline hydrolysis These compounds are new valuable starting maa sapogenin fraction which is dissolved in aceterials for the preparation of physiologically actone, treated with active-charcoal such a the arated from over a period of thirty minutes.

3 product known as Norite" and filtered. The clarified filtered acetone solution contains the sapogenin fraction of the plant and can be septhe acetone by evaporating the latter. Such sapogenin fractions consist of mixtures of sapogenins: The individual sapogenins are next isolated or separated out of this fraction.

The above description is mixture. It is merely illustrative and is capable of considerable variation, as will be understood by those skilled in the art. Any known sapogenin hydrolytic and procedures may vided solvents are used which liberated by the hydrolytic steps, Example. 1.'--Hecogenin from Agave, .toumeyana a 1 .Trel

5 kg. of medium age plants of the species Agave toumeyana Trel., collected above the tunnel on route 60-70, east of Superior, Arizona, in Novemtreated by the above described general procedurein'or'der to obtain a I sapog'e iractionlwhich consists largely of hecogenin, the starting material for the synthesis of rockogenin described in Example 2. The sapogenin fraction from ether is acetylated and crystallized'irom methanol-ethyl acetate togive plates of hecogen'in acetate, M. P. 246-2482 Yield, 13g.

Anal.: Calcd for Casi-14405: C, 73.7; H, 9.4. Foundi 0,755.4; H, 9.3.'f

"The acetate ishydr'olyzed and the product'is crystallized from methanol, M. P, 265-268". ".AnaL-z- Calcd for CwzHizOra' C, 75.35 H, 9.8; FoundiC, 75.0; H, 9.7, l Example 2.-Synthesis of rockogenin from hecogenin (a) By catalytic hydrogenatiom- -An ethereal solution of 0.3 g. of hecogenin containing several drops of acetic acidis shaken with.hydrogenfand 0.2 .g. of. Adams atalyst for twohoursat room temperature 'and three atoms. After filtering the solvent islrenioved. I The oily residue is refluxed with acetic anhydrideror one hour. The solvent is removed in vacuo on the steam bath androckogenin'fdiacetate is crystallized from methanol as long needles, M. P. 204-206"; yield, 0.12 g. j 1 Calcd' ior C31H4a0a2, C, 72.1; H, 9.4. Found: C,71.9';H, 9.2. f When hydrolyzed 'with5% alcoholicpotassium hydroxide for twenty minutes on the steam bath, the 'diacetate is .--converted' to the" rockog'enin which crystallizes" from methanol as dies, M. P."208-210. Repeated crystallizations from ether gives material melting 217-2202 'AnaLYCalcd for (1211714404? C, 75.0; H, 10.3. Found: C, 74.5; H, 10.2;

" '(b) By sodium-ethanol 1' tion of 300mg-of hecogenin ethanol is added 7 'g. of 'sodium'insmall strips The mixture is auction- T6 a soldcooled and poured r solid is extracted with ether and theethereal solution is washed with water, 10% hydrochloric acidand water. The eth'erealsolution is con centrated 233-244, wt, 160 mg. :Recrystallization from ether gives starting material melting260-262"; a

(265) melted 262-265.

a general procedure which I use for obtaining a sapogenin fraction or.

in 100 cc. of absoluteand cooled to give white crystals, M. P.

10 methanol as white needles,

methodior,

make possible the I the plant tissue of ketone subv ofhecogen in is shaken with hydrogen latter Calcd for Carl-14204: Found: C, 74.9; H, 9.8.

The first mother liquor is evaporated to dryness. The residue is from methanol as whitecrystals, M. P. and n ixedlvl, P. with rockogenin from (a), 209-210;" yieldsome: 1

Ariel; 'Calcd'for C2'IH4I4O4: C, 75.0","H, 10.3. Found: C, 74.9; H, 10.4,

The diacetate is prepared with boiling acetic anhydride .and the product is crystallized from M. P. and mixed 15.1.

with rockogenin diacetate from (a), M P. 205- .2070.

'Analxi Calcd' fo'r CnHmOa: C, 72.1; H, 9.4.

hecogenin aceg. of the acetate and Adams above. Rockogenin 3-monofrom methanol as white (0) Rockogem'n acetate from tate.--An ethereal solution of 0.5

catalyst as described acetate crystallizes pl'ates.M.-P. 2l1-213. v Anal; Calcd for Cad-14605; C, 734; H,.' 9.8. Found: C, 73.8; H, 9.7. v When refluxed wi h acetic anhydride for one diacetate, 1M. '2. and

hour it forms rockogenin mixed M. P., 203-205. Example 3.--Szmth.esis of hecogenone (a) Fnom hec0genin.-A solution of 0.1 g. or hecogenin in 30 cc. of acetic acid is mixed with a solution of 0.1 g. of chrornlc anhydride in 5 cc. acetic'acid. After standing thirty minutes at 25, water is added and the product is ether extracted. An alkali wash of the ethereal solution followed by acidificationv the aqueous layer gives no acid fraction. The ethereal solution is concentrated and cooled to give white needles of hecogenone, M. P, 237-240. AnaL: Calcd for CmHmOr. C, 75 Found: C, 75.5; H, 9A. I, (5) From rockogeflirlL -The above mother liquor from the preparationfoi rockogenin by catalytic reduction'of hecogenin described under, Example The residue dise solved in 25 cc. of acetic acid is oxidized with a solution of 0.15 g. of chromic anhydride in 10 cc. of acetic acid for thirty minutes at 20. The product is isolated as described above and crystallized from ether as white needles, M. P. and mixed M. P. with hecogenone, 237-240; yield 0.1 g.

Anal: Calcd for Carl-140042 Found: C, 7.5.5; H, 9.4,. I

Hecogenone "h ielew s s uctur 2.- mula- Ring dihydroxy compounds-,such as ro kosenin. can be diacylated at the ring hydroxyls' and partially saponifled .to obtain a mono-acylated hydroxy derivative which can then be oxidized withchromic acid at the free hydroxyl'to give the corresponding monoacylated ketone.

acylated ketone-upon hydrolysis gives the gas The monoacylated ketone can be hydrolyzed to the free hydroxy keto e, for example by methanolic potassium hydroxide.

What I claim is:

1- A crz-substituted steroidal sapogenln 01' the formula,

on cH a] :CH

Where X and Y are member of the class =0,

H and ester groups hydrolyzable to A C1zketo steroidal sapogenin of the formula,

O CH: CHHCH: OH: I CH: 4}

HC\ CH-CH:

was, I X A where X is a member of the class =0,

and ester groups hydrolyzable to 3. The new steroidal sapogenln, roekogemn, 01' the formula,

4. The new steroidal sapogenln compound having the formula,

on O CH f I CH-C CHr-CH:

CH-CH! 5. The method of synthesizing rockogenln which comprises reducing hecogenin having the formula ROMEO B. WAGNER. 

